Cardiovascular disease if the leading cause of death for both men and women in the U.S. today and claims more lives each year than the next five leading causes of death combined.
In the United States, nearly 5 million patients have been diagnosed with heart failure. Each year more than 500,000 new cases are recognized. This represents, by far the fastest growing area of cardiology. As many as 20% of these patients qualify for an implanted device, either an implantable pacemaker or implantable cardiac defibrillator (“ICD”) or a biventricular pacemaker/ICD, and a fortunate percent of those severely symptomatic individuals will go on to cardiac transplant.
The primary diagnoses associated with heart transplantation are coronary artery disease (45%) and cardiomyopathy (45%), with congenital heart disease accounting for 8% and approximately 3% for retransplantation.
Each year approximately 2,500 cardiac transplants are performed in the United States and this number approaches 5,000 worldwide. One-year survival is approximately 85% in experienced transplant centers, with a five-year survival rate approaching approximately 70%. The most common cause of death is infection, followed by acute rejection. Although technology exists to treat bradycardia and tachycardia, i.e., pacemakers and defibrillators, respectively, the currently available apparatus and methods for monitoring a transplanted heart or for assisting in congestive heart failure assessment are quite limited and, for the most part, require the patient to undergo extensive invasive procedures or repetitive visits to a hospital or other medical facility which can be expensive.
Known methods for monitoring patients who receive a heart transplant generally involve an invasive procedure called endomyocardial biopsy (“EMB”). EMB procedures typically require an invasive biopsy of the transplanted heart in which the patient is taken to a catheterization laboratory and a large blood vessel (usually in the neck) is cannulated allowing a biopsy catheter to be advanced into the right side of the heart. Several small pieces or bites of the myocardium are sampled during the EMB, which are then sent for pathological evaluation. Similar invasive procedures are required of patients suffering from congestive heart failure, including catheterization to evaluate pressures inside the heart.
As discussed above, the rejection of a transplanted heart by the patient's body is one of the leading causes of death during the first year following the transplant. In order to detect early rejection of a transplanted heart, multiple EMBs are performed at regular, predetermined intervals. The typical patient undergoes up to twenty (20) EMBs during the first year. After the first year, even patients who have not experienced a rejection episode continue to require periodic EMBs to insure normal function of the transplanted heart. Although EMBs detect rejection and allow treatment in order to prevent death of the transplant patient, EMBs themselves result in a substantial risk of bleeding, infection, cardiac perforation, and other morbidities including death. In addition, this catheterization procedure is not only costly, but also painful and inconvenient for the patient.
Medical practitioners have attempted to reduce the risks associated with EMBs by exploring alternative methods for predicting transplant rejection and/or complications from congestive heart failure. For example, during the last decade investigators in Europe focused on intramyocardial electrograms and immune system markers that had the potential for predicting ischemia as well as acute transplant rejection. In studies on canines evaluating data from four myocardial sites, it was found that analysis of the mean intramyocardial unipolar peak-to-peak R-wave amplitude had a sensitivity (i.e., an ability to identify rejection) and a specificity (i.e., percentage of false positives) sufficient for diagnosing most transplant rejection. It also was discovered that, as the number of myocardial leads increases (i.e., the number of myocardial sites monitored increases), the sensitivity of detecting transplant rejection also increased. Preliminary studies on humans were able to show a correlation between acute rejection episodes and the mean amplitude of the R-wave of the QRS complex.
Over the past fifteen years, more than one thousand prototype unipolar, peak-to-peak rejection monitors (“UPPRMs”) have been implanted in both adults and children. UPPRMs require two or more electrodes attached to the patient's heart that are structured to register QRS voltage. The amplitude measurement of the intramyocardial electrogram (“IMEG”) was used to predict rejection.
Another method of conventional rejection monitoring is disclosed in U.S. Pat. No. 5,246,008 to Mueller, which is incorporated herein. As disclosed in Mueller, the rejection monitor (“RM”) or telemetry measuring unit preferably is connected to the patient's heart using two pairs of current and measuring electrodes in which each current electrode is annularly surrounded by a measuring electrode. This RM includes a miniaturized, battery-operated electronic measuring circuit for impedance measurement. The RM also has a transmitter-receiver circuit for electromagnetic waves with a carrier frequency of one coil being able to function as the antenna. An AC voltage is applied in a square-wave pulse to the tissue via the current electrodes. The impedance of the body tissue is then measured via the measuring electrodes. The receiver coil of a telemetry control unit can be disposed on the body of the patient over the RM, preferably during the night rest periods. The control unit transmits an ON signal via the receiver coil to the RM via the antenna. The RM then begins applying AC voltage in a square-wave pulse utilizing the current electrodes and measuring the impedance via the measuring electrodes. The RM transmits the measured values for a predetermined measuring duration via the induction coupling formed by the antenna and receiver coil to the control unit. The measured values are stored by the control unit, such as on a computer, and values can be called in by a clinic using a modem via a telephone line.
As disclosed in Mueller, the impedance consists substantially of the ohmic resistance and a capacitive reactance. The ohmic resistance depends substantially on the extracellular space of the tissue, whereas the capacitive reactance depends substantially on the properties of the cell membrane. As a result of ischemia of the tissue during a rejection reaction, intracellular edema with simultaneous shrinkage of the extracellular space occurs, which results in changes to the ohmic resistance and capacitive reactance of the tissue. The change of the pulse form of the ac voltage is a measure of the impedance. If a square-pulse voltage is used as the ac voltage, the change of the pulse height corresponds to the ohmic resistance, whereas the change in the steepness of the leading edges of the square-wave pulses is a measure of the capacitive reactance.
Results have suggested several advantages of these alternative methods over current methods of transplant rejection assessment such as EMBs. In particular, UPPRMs enabled reliable recognition of transplant rejection episodes at an early stage, thus allowing prompt treatment to reverse rejection and to block further development to more severe stages. Because advanced stages of transplant rejection were not encountered, the amount of additional immuno-suppression necessary to terminate rejection was moderate thereby reducing the treatment costs. Compared to an eighty-five percent (85%) survival rate for one-year post transplant when EMBs are used to assess transplant rejection, there were no deaths from acute transplant rejection when UPPRMs was used to assess rejection, provided the patient adhered strictly to short-interval, and preferably daily, IMEG recording. Biopsy findings showed the IMEGs to have one hundred percent (100%) sensitivity and ninety-seven percent (97%) specificity in detecting transplant rejection and there were 3% false negatives. In those few cases when the UPPRMs indicated transplant rejection with negative biopsy results (reason for less than one hundred percent (100%) specificity), all of these patients went on to have transplant rejection within twenty-four (24) to forty-eight (48) hours.
However, simple IMEG amplitude measurement is subject to variation due to the patient's daily rhythm, exercise status, and medications. A drop in amplitude may not always correlate to a rejection reaction. Moreover, because conventional UPPRMs provide at best only periodic monitoring (i.e., only while the patient is sleeping) the IMEG data registered by the UPPRMs does not provide the best data for determining a rejection reaction.
In light of the foregoing, it would be highly desirable to provide methods and apparatus capable of eliminating the risks associated with EMBs while at the same time providing more comprehensive data regarding the function of a patient's heart. Specifically, the methods and apparatus should allow for continuous, non-invasive monitoring of a patient's heart to thereby accurately detect heart rejection or failure at its earliest phase. In addition, the apparatus and methods should preferably enable medical personnel to obtain historic and real-time monitoring data and information about the patient's heart so that the medical personnel can more effectively diagnose, discuss, coordinate or alter the patient's treatment.